Method for treating fungal infection in mammals with imidazo [1,2-a]quinoxalines

ABSTRACT

A method for treating a fungal infection in mammals which comprises administering to said mammals having a fungal infection a therapeutically effective amount of a 4-(substituted phenyl)imidazo[1,2-a]quinoxaline.

RELATED CASES

This is a continuation-in-part of application Ser. No. 757,640 filedJan. 7, 1977, now abandoned.

This invention relates to certain 4-substitutedimidazo[1,2-a]quinoxalines and to processes for preparing the same. Italso concerns certain 1-(2-acylaminophenyl)imidazoles which among otherthings are useful as intermediates in the preparation of 4-substitutedimidazo[1,2-a]quinoxalines. The aforesaid compounds are useful for avariety of purposes which will be described in more detail below. Someof these are useful as immunosuppressants; whereas, others are useful asanti-inflammatory agents or display antifungal activity. Moreover, someexhibit two or all three of these activities.

The 4-substituted imidazo[1,2-a]quinoxalines encompassed in the presentinvention may be described by the formula: ##STR1## and pharmaceuticallyacceptable salts thereof wherein X is --R¹ or --NHR² wherein:

(1) R¹ is bonded to a ring carbon by a carbon-to-carbon linkage and isan aliphatic, cycloaliphatic, substituted phenyl, fused bicyclic aryl;or monocyclic aryl-substituted aliphatic; and

(2) R² is a radical bonded to a nitrogen by a carbon to nitrogenlinkage; said radical being selected from the group consisting ofaliphatic, cycloaliphatic, phenyl, substituted phenyl, fused bicyclicaryl or a monocyclic aryl-substituted aliphatic group.

When R¹ is an aliphatic group, it may be a straight chain or branchedchain hydrocarbon group which is saturated, monounsaturated orpolyunsaturated. It may also comprise a straight chain or branched chaingroup containing other than carbon-to-carbon bondings e.g. etherlinkages, carbon to halogen linkages, etc. Ordinarily, it will containfrom about 1 to 18 carbon atoms, the most typical radicals of this groupbeing the alkyl radicals having from 1 to 18 carbon atoms.

By way of illustrating the aliphatic groups that may be represented byR¹, the following are given: CH₃ --; CH₃ CH₂ --; CH₃ CH₂ --CH₂ --; CH₃(CH₂)_(n) -- in which n is 3, 4, 5, 6, 7, 8, 14 and 16 respectively;(CH₃)₂ CH--CH₂ --; CH₃ (CH₂)₃ (CH₃ CH₂)CH--, CH₂ ═CH--(CH₂)₈ --,alkoxyalkyl in which the alkyl moieties have from 1 to 4 carbon atomse.g. methoxymethyl; halogenoalkyl (i.e. CH₂ Cl--; CH₃ CHCl--; CHCL₂ --;CCl₃ --; CH₂ Br--; CF₃).

When R¹ is a cycloaliphatic radical it will most often be a cycloalkylradical containing 3 to 8 carbon atoms or a cycloalkenyl radicalcontaining 5 to 6 carbon atoms. By way of illustrating thecycloaliphatic radicals that may correspond to R¹ in formula I mentionmay be made of the cyclopropyl ##STR2## cyclobutyl ##STR3## cyclohexyl,cyclohexenyl ##STR4## and norbornenyl ##STR5##

When R¹ is a substituted phenyl radical in formula I above, the phenylgroup may have from 1 to 5 substituents but will usually be mono, di ortrisubstituted. Typical among the groups that may be contained in thephenyl group are (a) alkyl groups which are branched or straight chaincontaining 1 to 6 carbon atoms e.g. methyl, ethyl, tertiary butyl; (b)alkoxyl groups containing 1 to 6 carbon atoms e.g. methoxy, ethoxy; (c)hydroxy; (d) acyloxy containing 1 to 18 carbon atoms; (e) halogen e.g. 1or 2 Cl, F, Br, I preferably in the meta and/or para position; (f)nitro; (g) amino; (h) acylamino in which the acylamino moiety is derivedfrom an alkanoic acid containing 1 to 18 carbon atoms and benzamides inwhich the benzene ring is unsubstituted or monosubstituted,disubstituted or trisubstituted with alkyl groups containing 1 to 5carbon atoms or halogen atoms; (i) polyhydroxyalkylamino groupscontaining 4 to 8 carbon atoms; (j) cyano; (k) trifluoromethyl; (l)mercapto; (m) alkylthio; (n) acylthio containing 1 to 18 carbon atoms;(o) carboxyl; (p) carboalkoxyl containing 1 to 8 aliphatic carbon atoms;(q) phenyl; (r) phenoxy, and combinations thereof.

When R¹ is a fused bicyclic aryl radical, it may be a substituted orunsubstituted radical. These are exemplified by such fused bicyclichydrocarbon radicals as 1-naphtyl, 2-naphthyl etc.

When R¹ is a monocyclic aryl substituted aliphatic radical, themonocyclic aryl moiety may be either of the substituted or unsubstitutedvariety. The aliphatic moiety of this group may be either of thesaturated or unsaturated straight chain or branched chain hydrocarbonvariety or it may contain other than carbon-to-carbon bonding. This maybe illustrated by such groups as phenoxymethyl; benzyl, styryl, ##STR6##

The group R² in the radical -NHR² of formula I above is exemplified bythe same radicals given above in illustrating the radical -R¹. Inaddition, R² may also be phenyl as in the case of the group ##STR7##

In general, the compounds included in formula I above as well as thecases in formula I in which X is hydrogen or phenyl may be prepared byheating the corresponding 1-(2-acylaminophenyl)imidazole at reflux inthe presence of cyclizing quantities of a cyclizing agent e.g.polyphosphoric acid or phosphorous oxychloride, etc. for sufficient timeto cause significant cyclization of this reactant. More particularly,the 1-(2-acylaminophenyl)imidazole reactants that can be employed inthis process may be described by the general formula: ##STR8## in whichX² is R⁵ or --NHR² wherein: R⁵ is hydrogen or an aliphatic,cycloaliphatic, phenyl or substituted phenyl, fused bicyclic aryl ormonocyclic aryl substituted aliphatic radical and R² has the same valuesassigned to it in connection with formula I above.

The group R⁵ in formula II is illustrated by the same groups thatillustrate R¹ in formula I. However, in addition, R⁵ may also beillustrated by the phenyl radical.

The reaction can be depicted by the following equation: ##STR9##

The process of equation III is preferably carried out in the presence ofan excess of an organic amine solvent. A variety of solvents may be usedfor this purpose among which mention may be made of the following:pyridine, 2,6-dimethylpyridine, N,N-dimethylaniline, trimethylamine, andN-methylmorpholine, etc. However, the preferred organic solvent ispyridine.

The quantity of phosphorous oxychloride that is employed in the reactioncan vary somewhat. Generally, however, the phosphorous oxychloride willbe employed in the range of from about one-half mole to about 6 molesand preferably one-half mole to two moles per mole of compound II.

The desired product IV may be recovered from the reaction mixture usingany of the ordinary techniques well known to those skilled in this art.The time of reaction will vary depending upon, among other things, theparticular reactants or molar quantities of reactants employed. Ingeneral, the reaction time will be from about 30 to 120 minutes.

The temperature employed in carrying out the reaction will also varydepending upon the particular reactants selected, the solvent and otherfactors. Ordinarily, the temperature employed will be the refluxtemperature of the reaction mixture. This generally will be in the rangeof from about 95° C. to 195° C.

The method of preparing the 1-(2-acylaminophenyl)imidazoles (compoundII) will vary depending on the particular type that is being made. Thus,for example, in preparing compound of the general type: ##STR10## whereR⁵ is hydrogen, aliphatic, cycloaliphatic, phenyl, substituted phenyl,fused bicyclic aryl or monocyclic aryl substituted aliphatic group, the1-(2-acylaminophenyl)imidazole is reacted with the appropriate acidhalide e.g. the acid chloride.

This can be expressed by the following equation: ##STR11## in which R⁵has the value ascribed to it above. The reaction will usually be carriedout employing equimolar amounts of the appropriate acid chloride and inthe presence of excess solvent (e.g. pyridine) at reflux.

When the compounds in question are of the phenylureylene type e.g.##STR12## where R² is hydrogen, aliphatic, cycloaliphatic, phenyl,substituted phenyl, fused bicyclic aryl or monocyclic aryl substitutedaliphatic group, these are prepared by reacting the aminophenylimidazolewith the appropriate isocyanate. This can be expressed by the followingequation: ##STR13## in which R² has the value ascribed to it above. Thisreaction is preferably carried out in the presence of a solvent and atsteam bath temperatures. A typical solvent that can be employed istoluene and the reactants are usually used in about equimolarquantities. The products obtained from reactions VI and VIII may berecovered using standard techniques well known to those skilled in thisart.

Prior Art

U.S. Pat. No. 3,887,566 discloses imidazo[1,2-a]quinoxaline and4-phenylimidazo[1,2-a]quinoxaline. However, this reference does notdisclose the 4-substituted imidazo[1,2-a]quinoxalines of the presentinvention nor the process for making these compounds. The activitydisclosed in this reference for these compounds is as cardiovasculardrugs. There is no disclosure of the fact that these compounds may haveimmunosuppressant activity, antifungal activity or non-steroidalanti-inflammatory action. It is in fact interesting to note that theunsubstituted imidazo[1,2-a]quinoxaline lacks immunosuppressant activitywhile the 4-phenylimidazo[1,2-a]quinoxaline has only minor activitywhich is greatly increased by substitution on the para- and meta-positions on the benzene ring.

Uryukina et al, Khim. Geterotsikl. Soedin., 1972, 1558-60 (See C.A. 78,58345^(t) (1973) discloses the unsubstituted and the 7-methyl, methoxy,and bromo substituted imidazo[1,2-a]quinoxalines. No 4-substitutedproducts are disclosed nor is any utility disclosed for these compounds.

Kovalev et al, Farmakol. Toksilkol (Moscow), 36 (2), 232-238, 1973 (SeeC.A. 78 154693^(a)) also discloses the7-methoxyimidazo[1,2-a]quinoxaline and suggests the use of this materialas an hypotensive agent. This reference likewise does not disclose the4-substituted imidazo[1,2-a]quinoxalines of the present invention ortheir utility.

Japanese Patents 10677/74 and 10678/74 disclose certain 4-substituted1,2-dihydroimidazo[1,2-a]quinoxalines and the fact that these materialsare useful as anti-inflammatory agents. These references do not show theunhydrogenated compounds of this invention. Moreover, noimmunosuppressant activity or antifungal activity is disclosed.

Siminov et al, Khim. Geterotsikl, Soedin, 7, 570 (1971) (See C.A. 76,25242^(n) 1972) discloses a process for synthesizingimidazo[1,2-a]quinoxaline involving the reduction of1-(o-nitrophenyl)-2-formylimidazole. This is obviously not related tothe process of the present invention.

The following Examples are given to further illustrate the presentinvention. It is to be understood, however, that they are not limitativeof this invention.

The compounds described in the Tables below were prepared as described.Melting points were obtained by the capillary tube method using aMel-Temp melting point apparatus and are uncorrected. Ultravioletspectra were obtained in ethanol solution using a Beckman U.V. Acta IIIor a Beckman DBG. 1-(2-aminophenyl)imidazole was prepared as reported byA. F. Pozharskii, A. M. Siminov and L. M. Sitkina, Khim. Geterotskl.Soedin. 5, 1916 (1969) [Chem. Abstr., 72 11427^(a) (1970)].

Table I below further illustrates the preparation of the aliphatic,cycloaliphatic and monocyclic aryl substituted aliphatic-amidophenylimidazoles of the present invention. Table II furtherexemplifies the preparation of the aryl (including the fused ring aryl)amidophenylimidazoles of this invention.

Except as noted in Tables I and II, the amides were prepared by reactingequimolar amounts of the appropriate acid chloride with1-(2-aminophenyl)imidazole in the presence of excess pyridine on a steambath for 45 minutes. The reaction mixture was then stirred into icewater and the crude product isolated according to one of the followingmethods.

Method A

If a solid was obtained, it was directly crystallized from the solventindicated in Table I.

Method B

If an oil was obtained, it was dissolved in a minimum amount ofchloroform and passed through an alumina column with the amount ofalumina being approximately twenty times the weight of the crude solid;elution was with chloroform. The chloroform was evaporated from thecrude product which was crystallized as indicated in Table I.

Method C

If a solution was obtained in the ice water mixture, the pyridine/waterazeotrope was removed until the crude product separated. It was thentreated as in Method B above.

                                      TABLE I                                     __________________________________________________________________________     ##STR14##                                                                    1-(2-alkanamidophenyl)imidazoles                                                                       Isolation                                                                           %   Crystallization Analysis                   No.  R                   Method                                                                              Yield                                                                             Solvent   m.p., °C.                                                                    Calc'd                                                                              Found                __________________________________________________________________________    1    H.sup.a             C     63.3                                                                              Water     200-204                                                                             C,64.16                                                                             64.26                                                                   H, 4.85                                                                              4.71                                                                   N,22.45                                                                             22.30                2    CH.sub.3            A     56.2                                                                              Ethanol   163-166                                                                             C,65.66                                                                             65.69                                                                   H, 5.51                                                                              5.52                                                                   N,20.88                                                                             20.84                3    CH.sub.3 CH.sub.2.sup.b                                                                           C     73.9                                                                              Water     144-146                                                                             C,66.96                                                                             67.26                                                                   H, 6.09                                                                              6.15                                                                   N,19.52                                                                             19.40                4    CH.sub.3 (CH.sub.2).sub.2                                                                         B     31.1                                                                              Toluene   108-110                                                                             C,68.10                                                                             67.95                                                                   H, 6.59                                                                              6.52                                                                   N,18.33                                                                             18.25                5    CH.sub. 3 (CH.sub.2).sub.3                                                                        B     49.6                                                                              Toluene-  123-125                                                                             C,69.11                                                                             69.14                                                   hexane          H, 7.04                                                                              7.00                                                                   N,17.27                                                                             17.17                6    CH.sub.3 (CH.sub.2).sub.4                                                                         B     49.4                                                                              isopropyl ether-                                                                        103-105                                                                             C,70.01                                                                             70.31                                                   trichloroethylene                                                                             H, 7.44                                                                              7.45                                                                   N,16.33                                                                             16.26                7    CH.sub.3 (CH.sub.2).sub.5                                                                         A     55.3                                                                              isopropyl ether                                                                         96-98 C,70.82                                                                             70.79                                                                   H, 7.80                                                                              7.74                                                                   N,15.48                                                                             15.23                8    CH.sub.3 (CH.sub.2).sub.6                                                                         A     55.1                                                                              isopropyl ether                                                                         101-102                                                                             C,71.55                                                                             71.67                                                                   H, 8.12                                                                              8.05                                                                   N,14.72                                                                             14.65                9    CH.sub.3 (CH.sub.2).sub.7                                                                         A     45.6                                                                              isopropyl ether                                                                         93-95 C,72.21                                                                             72.24                                                                   H, 8.42                                                                              8.41                                                                   N,14.03                                                                             13.92                10   CH.sub.3 (CH.sub.2).sub.8                                                                         A     60.6                                                                              isopropyl 79-81 C,72.81                                                                              73.38                                                  ether-hexane    H, 8.68                                                                              8.85                                                                   N,13.41                                                                             13.02                11   CH.sub.3 (CH.sub.2).sub.14                                                                        B     58.1                                                                              isopropyl ether                                                                         94-96 C,75.52                                                                             75.12                                                                   H, 9.89                                                                              9.76                                                                   N,10.57                                                                             10.38                12   CH.sub.3 (CH.sub.2).sub.16                                                                        B     80.6                                                                              isopropyl ether                                                                         98-100                                                                              C,76.19                                                                             76.57                                                                   H,10.18                                                                             10.28                                                                   N, 9.87                                                                              9.79                13   (CH.sub.3).sub.3 C .sup.b                                                                         C     48.8                                                                              benzene   102-104                                                                             C,69.11                                                                             69.15                                                                   H, 7.04                                                                              7.26                                                                   N,17.27                                                                             17.19                14   (CH.sub.3).sub.2 CHCH.sub.2                                                                       C     25.4                                                                              benzene   128-130                                                                             C,69.40                                                                             69.60                                                                   H, 6.66                                                                              7.00                                                                   N,17.34                                                                             17.40                15   CH.sub.3 (CH.sub.2).sub.3 (CH.sub.3 CH.sub.2)CH                                                   B     32.8                                                                              benzene   125-127                                                                             C,71.55                                                                             71.86                                                                   H, 8.12                                                                              7.84                                                                   N,14.72                                                                             14.95                16   CH.sub.2CH(CH.sub.2).sub.8                                                                        A     76.8                                                                              isopropyl 92-94 C,73.81                                                                             74.26                                                   ether-hexane    H, 8.36                                                                              8.50                                                                   N,12.91                                                                             12.30                17   CH.sub.3 (CH.sub.2).sub.3 (CH.sub.2CHCH).sub.2 (CH.sub.2).sub.7                                   C     3.6 c.        73.76 C,76.92                                                                             76.73                                                                   H, 9.32                                                                              9.36                                                                   N, 9.97                                                                              9.78                18                                                                                  ##STR15##          C     41.9                                                                              ethanol   145.147                                                                             C,73.63 H, 5.45                                                               N,15.15                                                                             73.81  5.57                                                                   15.41                19                                                                                  ##STR16##          C     7.7 diethyl ether                                                                           205-207                                                                             C,74.73 H, 6.27                                                               N,13.76                                                                             74.83  6.32                                                                   13.59                20                                                                                  ##STR17##          A     43.0                                                                              ethanol   161-164                                                                             C,74.72 H, 5.23                                                               N,14.52                                                                             74.94  5.47                                                                   14.55                21   CH.sub.3 OCH.sub.2  A     49.8                                                                              Toluene   146-147                                                                             C,62.33                                                                             61.99                                                                   H, 5.66                                                                              5.74                                                                   N,18.17                                                                             18.48                22                                                                                  ##STR18##          A     77.7                                                                              Toluene   136.5- 138.5                                                                        C,69.61 H, 5.15                                                               N,14.33                                                                             69.82  5.37                                                                   14.04                23                                                                                  ##STR19##          A     10.1                                                                              isopropanol                                                                             207-209                                                                             C,68.71 H, 5.76                                                               N,18.49                                                                             68.67  5.85                                                                   18.67                24                                                                                  ##STR20##          A     55.6                                                                              Toluene   151-153                                                                             C,69.69 H, 6.27                                                               N,17.41                                                                             69.44  6.21                                                                   17.55                25                                                                                  ##STR21##          A     67.3                                                                              Toluene   142.5- 145                                                                          C,71.35 H, 7.11                                                               N,15.60                                                                             70.88  6.92                                                                   15.59                26                                                                                  ##STR22##          A     21.6                                                                              ethanol   196-198.5                                                                           C,72.16 H, 6.06                                                               N,15.78                                                                             71.87  6.33                                                                   15.40                27   CH.sub.2 Cl         B     11.9                                                                              water     255(dec.)                                                                           C,56.06                                                                             55.92                                                                   H, 4.28                                                                              4.26                                                                   N,17.83                                                                             17.72                28   CH.sub.3 CHCl       A     27.9                                                                              Toluene   143.5-                                                                              C,57.72                                                                             57.54                                                             145.5°                                                                       H, 4.85                                                                              4.92                                                                   H,16.83                                                                             17.16                29   CHCl.sub.2.sup.b    A     33.2                                                                              benzene   162-165                                                                             C,48.91                                                                             48.94                                                                   H, 3.36                                                                              3.24                                                                   N,15.56                                                                             15.42                                                                   Cl,26.25                                                                            26.17                30   CF.sub.3            A     22.0                                                                              ethanol   165-167                                                                             C,51.77                                                                             51.58                                                                   H, 3.16                                                                              3.20                                                                   N,16.47                                                                             16.53                32                                                                                  ##STR23##          C     14.1                                                                              trichloro- ethylene                                                                     128-130                                                                             C,60.23 H, 5.05                                                               N,16.21                                                                             60.21  5.10          __________________________________________________________________________                                                             16.16                 Notes:                                                                         a. Prepared from aceticformic anhydride according to R. J. Jones, J. Am.     Chem. Soc., 71,644(1949). After removal by distillution of excess solvent     residue dissolved in water and neutralized with NaOH to provide crude         product.                                                                       b. Prepared via the anhydride.                                                c. Could not be crystallized; purified by chromatography on alumina with     ethyl acetate as elutant.                                                

                                      TABLE II                                    __________________________________________________________________________     ##STR24##                                                                    1-(2-Arylamidophenyl)imidazoles                                                                Isolation                                                                          %   Crystallization           Analysis                  No. Ar           Method                                                                             Yield                                                                             Solvent   m.p., °C.                                                                     λmax.(Am)                                                                       Calc'd                                                                              Found               __________________________________________________________________________    34                                                                                 ##STR25##   A    44.9                                                                              dimethoxyethane                                                                         148-150                                                                              225(21,720)                                                                            C,72.99 H, 4.98                                                               N,15.96                                                                             73.30  5.08                                                                   16.04               35                                                                                 ##STR26##   A    58.7                                                                              ethanol   190-192.5                                                                            262(21,400)                                                                            C,73.63 H, 5.45                                                               N,15.15                                                                             73.10  5.32                                                                   15.46               36                                                                                 ##STR27##   B    58.3                                                                              benzene   147-148.5                                                                            231,sh(18,200)                                                                         C,73.63 H, 5.45                                                               N,15.15                                                                             73.63  5.24                                                                   15.36               37                                                                                 ##STR28##   B    57.4                                                                              benzene   143-146.5                                                                            236(23,400)                                                                            C,73.63 H, 5.45                                                               N,15.15                                                                             73.28  5.29                                                                   15.27               38                                                                                 ##STR29##   A    53.0                                                                              benzene   151-153                                                                              c.       C,61.63 H, 3.65                                                               N,12.68                                                                             60.97  3.62                                                                   12.34               39                                                                                 ##STR30##   B    79.3                                                                              ethyl acetate                                                                           136-138                                                                              239(20,400)                                                                            C,75.21 H, 6.63                                                               N,13.27                                                                             75.06  6.45                                                                   13.31               40                                                                                 ##STR31##   A    45.5                                                                              isopropanol                                                                             198-200                                                                              276(28,100)                                                                            C,77.86 H, 5.05                                                               N,12.38                                                                             77.46  4.76                                                                   12.09               41                                                                                 ##STR32##   A    73.5                                                                              dimethylformamide, ethanol                                                              194-196                                                                              260(17,810)                                                                            C,62.33 H, 3.92                                                               N,18.17                                                                             62.26  3.69                                                                   18.10               42                                                                                 ##STR33##   A    74.4                                                                              dimethylformamide, water                                                                198-202.5                                                                            250(16,500)                                                                            C,62.33 H, 3.92                                                               N,18.17                                                                             62.27  4.00                                                                   18.37               43                                                                                 ##STR34##   A    87.41                                                                             dimethylformamide, water                                                                254-256                                                                              c.       C,54.40 H, 3.14                                                               N,19.82                                                                             54.35  3.31                                                                   19.82               44                                                                                 ##STR35##   A    60.87                                                                             dimethylformamide, water                                                                219-220.5                                                                            234(1,500)                                                                             C,70.82 H, 4.20                                                               N,19.49                                                                             70.14  4.45                                                                   19.15               45                                                                                 ##STR36##   B    56.8                                                                              benzene   205-208                                                                              229(18,500)                                                                            C,68.32 H, 4.30                                                               N,14.94                                                                             67.86  4.02                                                                   15.17               46                                                                                 ##STR37##   A    53.2.sup.a                                                                        dimethylformamide, water                                                                93-96  260(10,100)                                                                            C,66.20 H, 4.51                                                               N,14.47                                                                             65.96  4.37                                                                   14.40               47                                                                                 ##STR38##   A    b.  dimethylformamide                                                                       189-190.5                                                                            240(22,100)                                                                            C,56.16 H, 3.53                                                               N,12.28                                                                             56.03  3.58                                                                   12.51               48                                                                                 ##STR39##   A    40.1                                                                              dimethylformamide, water                                                                199-201.5                                                                            258(20,100)                                                                            C,56.16  H, 3.54                                                              N,12.28                                                                             55.84  3.58                                                                   12.48               49                                                                                 ##STR40##   A    38.7                                                                              dimethylformamide, ethanol                                                              201-203                                                                              261(16,700)                                                                            C,64.54 H, 4.06                                                               N,14.11                                                                             64.70  4.05                                                                   13.95               50                                                                                 ##STR41##   B    68.5                                                                              ethanol   144-146                                                                              c.       C,64.54 H, 4.06                                                               N,14.11                                                                             64.82  3.92                                                                   14.59               51                                                                                 ##STR42##   A    59.7                                                                              ethanol   167-170                                                                              240(26,410)                                                                            C,64.54 H, 4.06                                                               N,14.11                                                                             64.41  3.94                                                                   13.92               52                                                                                 ##STR43##   A    26.6                                                                              dimethylformamide, water                                                                210-212                                                                              265(21,000)                                                                            C,57.85 H, 3.34                                                               N,12.65                                                                             58.05  3.46                                                                   13.08               53                                                                                 ##STR44##   A    61.2                                                                              dimethylformamide, water                                                                180.5-183                                                                            235(22,100)                                                                            C,57.85 H, 3.34                                                               N,12.65                                                                             57.65  3.51                                                                   12.93               54                                                                                 ##STR45##   A    42.9                                                                              ethanol   186.5-189                                                                            255(28,480)                                                                            C,49.38 H, 3.11                                                               N,10.80 I,32.61                                                                     49.22  3.15                                                                   10.85 32.89         55                                                                                 ##STR46##   B    58.6                                                                              isopropanol                                                                             146-151                                                                              263(20,400)                                                                            C,69.61 H, 5.15                                                               N,14.33                                                                             69.01  5.14                                                                   14.36               56                                                                                 ##STR47##   B    83.2                                                                              dimethylformamide, water                                                                171-173                                                                              281(5,100)                                                                             C,69.61 H, 5.15                                                               N,14.33                                                                             69.27  5.02                                                                   14.28               57                                                                                 ##STR48##   B    61.2                                                                              benzene   130-132.5                                                                            244,sh(12,300)                                                                         C,66.86 H, 5.30                                                               N,13.00                                                                             66.97  5.08                                                                   13.54               58                                                                                 ##STR49##   C    29.79                                                                             dimethylformamide, water                                                                133.5-136.5                                                                          281(15,410)                                                                            C,69.61 H, 5.15                                                               N,14.33                                                                             69.10  5.08                                                                   14.18               59                                                                                 ##STR50##   B    18.26                                                                             dimethylformamide, water                                                                164.5-166.5                                                                          c.       C,56.16 H, 3.54                                                               N,12.28                                                                             55.65  3.51                                                                   12.37               60                                                                                 ##STR51##   A    51.07                                                                             isopropanol                                                                             142.5-145.5                                                                          223(14,420)                                                                            C,68.32  H, 4.30                                                              N,14.94                                                                             67.79  4.36                                                                   14.58               61                                                                                 ##STR52##   B    15.68                                                                             isopropanol- ethanol                                                                    203.5-205                                                                            258(18,840)                                                                            C,54.40 H, 2.28                                                               N,11.90                                                                             53.78  2.30                                                                   12.16               62                                                                                 ##STR53##   A    46.9                                                                              isopropanol                                                                             165.5-167.5                                                                          237(53,900)                                                                            C,76.66 H, 4.83                                                               N,13.41                                                                             76.29  4.84                                                                   13.27               63                                                                                 ##STR54##   A    36.78                                                                             isopropanol- dimethylformamide                                                          175-177                                                                              289(6,940)                                                                             C,76.66 H, 4.82                                                               N,13.41                                                                             76.68  4.75                                                                   12.01               190                                                                                ##STR55##   B    38.80                                                                             benzene   156-157.5                                                                            268(13,800)                                                                            C,64.58 H, 5.42                                                               N,11.89                                                                             64.58  5.39                                                                   12.02               217                                                                                ##STR56##   A    45.8                                                                              ethanol   134-136.5                                                                            273(14,900)                                                                            C,66.86 H, 5.30                                                               N,13.00                                                                             66.88   5.37                                                                  12.68               __________________________________________________________________________     Notes:                                                                        a. isolated as hemihydrate.                                                   b. partial loss prevented yield determination.                                c. Compound absorbed too low for significant U.V.                        

Alkyl-2-(1-imidazolyl)phenylureylenes (Table III) were prepared by thereaction of equimolar amounts of the aminophenylimidazole and theappropriate isocyanate in toluene solution at steam bath temperaturesduring two or three hours. Upon cooling, the crude product was collectedby filtration and treated by one of the following methods: (A) directcrystallization from the appropriate solvent or (B) dissolved in hotdimethylformamide and precipitated with water followed bycrystallization.

                                      TABLE III                                   __________________________________________________________________________     ##STR57##                                                                    Alkyl-2-(1-imidazolyl)phenylureylenes                                                      Isolation                                                                          %   Crystallization        Analysis                         No.                                                                              R         Method                                                                             Yield                                                                             Solvent   m.p., °C.                                                                    λmax.(Am)                                                                     Calc'd                                                                             Found                       __________________________________________________________________________    64 CH.sub.3  A    41.6                                                                              ethanol   194-196                                                                             240(15,500)                                                                          C,61.60                                                                            61.22                                                                    H, 5.59                                                                             5.48                                                                    N,25.91                                                                            26.11                       65 CH.sub.3 CH.sub.2                                                                       B    27.3                                                                              trichloroethylene                                                                       173-175                                                                             278(1,200)                                                                           C,62.59                                                                            62.21                                                             242(12,700)                                                                          H, 6.13                                                                             6.04                                                                    N,24.33                                                                            24.32                       66 CH.sub.3 CH.sub.2 CH.sub.2                                                              B    49.3                                                                              trichloroethylene                                                                       139-141                                                                             279(1,200)                                                                           C,63.92                                                                            63.75                                                             240(12,800)                                                                          H, 6.60                                                                             6.56                                                                    N,22.93                                                                            23.00                       67 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                     B    35.6                                                                              isopropanol                                                                             115-116.5                                                                           278(1,400)                                                                           C,65.09                                                                            64.84                                                             241(15,000)                                                                          H, 7.02                                                                             7.00                                                                    N,21.69                                                                            21.78                       68                                                                                ##STR58##                                                                              A     50.64                                                                            dimethylformamide, water                                                                164-166                                                                             241(12,200)                                                                          C,67.58 H, 7.09 N,19.70                                                            67.60  7.08 19.44           __________________________________________________________________________

Aryl-2-(1-imidazolyl)phenylureylenes (Table IV) were prepared byreacting equimolar amounts of the aminophenylimidazole and theappropriate arylisocyanate in dry toluene during three hours at steambath temperatures. The reaction mixture was cooled and the crude productwas separated by filtration, and washed with ether and crystallized fromthe indicated solvent.

                                      TABLE IV                                    __________________________________________________________________________     ##STR59##                                                                    Aryl-2-(1-imidazolyl)phenylureylenes                                                                  Recrystallization       Analysis                      No. Ar              % Yield                                                                            Solvent   m.p., °C.                                                                      λmax.(Am)                                                                    Calc'd                                                                             Found                   __________________________________________________________________________    69                                                                                 ##STR60##      64.6 ethanol   201-203 256(27,640)                                                                         C,69.05 H, 5.07 N,20.13                                                            69.13  5.15 20.16       70                                                                                 ##STR61##      76.9 dimethylformamide- water                                                                203.5-207.5                                                                           258(23,400)                                                                         C,69.84 H, 5.52 N,19.17                                                            69.85  5.47 19.28       71                                                                                 ##STR62##      76.9 ethanol   182-183.5                                                                             256(25,800)                                                                         C,69.84 H, 5.52 N,19.17                                                            69.97  5.35 19.12       72                                                                                 ##STR63##      78.8 dimethylformamide- water                                                                202.5-203.5                                                                           251(25,500)                                                                         C,64.86 H, 4.42 N,18.91                                                            64.77  4.47 19.16       73                                                                                 ##STR64##      61.9 dimethylformamide- water                                                                201.5-202                                                                             253(26,000)                                                                         C,64.86 H, 4.42 N,18.97                                                            64.47  4.40 19.24       74                                                                                 ##STR65##      65.8 dimethylformamide- water                                                                220-222 251(23,100)                                                                         C,64.86 H, 4.42 N,18.97                                                            64.56  4.41 19.14       75                                                                                 ##STR66##      76.7 dimethylformamide- water                                                                204-206 258(30,900)                                                                         C,61.45 H, 4.19 N,17.91                                                            61.57  4.12 18.26       76                                                                                 ##STR67##      58.1 dimethylformamide- water                                                                244-245.5                                                                             260(32,900)                                                                         C,55.35 H, 3.48 N,16.14                                                            54.93  3.47 16.25       77                                                                                 ##STR68##      70.0 dimethylformamide- water                                                                180.5-182.5                                                                           252(23,000)                                                                         C,53.80 H, 3.76 N,15.68                                                            53.88  3.78 15.66       78                                                                                 ##STR69##      75.2 dimethylformamide- water                                                                218-219.5                                                                             258(28,600)                                                                         C,53.80 H, 3.67 N,15.68                                                            53.71  3.66 15.35       79                                                                                 ##STR70##      53.1 methanol  227-230.5                                                                             260(27,700)                                                                         C,53.80 H, 3.67 N,15.68                                                            52.08  3.56 15.12       80                                                                                 ##STR71##      83.2 dimethylformamide- water                                                                201-202 253(26,000)                                                                         C,64.86 H, 4.42 N,18.97                                                            64.47  4.40 19.24       81                                                                                 ##STR72##      57.79                                                                              dimethylformamide- water                                                                167-170 250(20,710)                                                                         C,69.84 H, 5.52 N,19.17                                                            70.10  5.57 18.60       82                                                                                 ##STR73##      77.4 dimethylformamide- water                                                                216.5-218.5                                                                           256(31,010)                                                                         C,58.96 H, 3.78 N,16.18                                                            58.86  3.81 15.79       83                                                                                 ##STR74##      78.9 dimethylformamide- water                                                                212-215 260(27,580)                                                                         C,70.57 H, 5.92 N,18.29                                                            70.30  5.83 18.00       84                                                                                 ##STR75##      76.6 dimethylformamide- water                                                                185-188 258(29,590)                                                                         C,70.57 H, 5.92 N,18.29                                                            70.30  5.96 18.00       85                                                                                 ##STR76##      76.2 dimethylformamide- water                                                                163.5-166                                                                             258(28,770)                                                                         C,70.57 H, 5.92 N,18.29                                                            70.52  5.81 17.94       86                                                                                 ##STR77##      67.8 dimethylformamide- water                                                                169-172 257(29,920)                                                                         C,71.83 H, 6.63 N,16.75                                                            71.61  6.56 16.24       87                                                                                 ##STR78##      80.6 dimethylformamide- water                                                                206-209 282(27,620)                                                                         C,71.23 H, 6.29 N,17.49                                                            71.12  6.12 17.24       88                                                                                 ##STR79##      69.0 dimethylformamide- water                                                                204.5-206                                                                             285(10,630)                                                                         C,66.22 H, 5.23 N,18.17                                                            65.96  5.15 18.15       89                                                                                 ##STR80##      84.0 dimethylformamide- water                                                                188     252(25,510)                                                                         C,66.22 H, 5.23 N,18.17                                                            65.83  5.13 18.02       90                                                                                 ##STR81##      81.9 dimethylformamide- water                                                                200-202 260(24,560)                                                                         C,66.22 H, 5.23 N,18.17                                                            65.61  5.14 17.98       91                                                                                 ##STR82##      80.9 dimethylformamide- water                                                                190.5-193                                                                             259(27,180)                                                                         C,67.07 H, 5.63 N,17.38                                                            66.80  5.62 17.16       92                                                                                 ##STR83##      79.5 dimethylformamide- water                                                                178-179.5                                                                             258(26,490)                                                                         C,68.55 H, 6.33 N,15.99                                                            68.68  6.34 15.62       93                                                                                 ##STR84##      64.1 dimethylformamide- water                                                                202.5-205                                                                             259(35,850)                                                                         C,71.34 H, 4.90 N,15.13                                                            71.14  4.93 14.78       94                                                                                 ##STR85##      75.1 dimethylformamide- water                                                                189-191 278(32,130)                                                                         C,62.94 H, 4.97 N,17.27                                                            62.84  4.86 17.22       95                                                                                 ##STR86##      62.3 dimethylformamide- water                                                                211.5-214.5                                                                           259(30,210)                                                                         C,61.45 H, 4.19 N,17.91                                                            60.94   4.02 17.79      96                                                                                 ##STR87##      75.9 dimethylformamide- water                                                                198-210 252(25,230)                                                                         C,61.44 H, 3.85 N,17.83                                                            61.33  3.92 17.98       97                                                                                 ##STR88##      64.8 dimethylformamide- water                                                                232.5-234                                                                             258(32,380)                                                                         C,55.35 H, 3.48 N,16.14                                                            55.60  3.50 16.00       98                                                                                 ##STR89##      70.7 dimethylformamide- water                                                                237.5-239                                                                             258(31,300)                                                                         C,62.48 H, 4.63 N,17.15                                                            62.79  4.70 17.30       99                                                                                 ##STR90##      70.0 dimethylformamide- water                                                                229-232 256(25,630)                                                                         C,58.10 H, 3.66 N,16.94                                                            57.84  3.56 16.90       100                                                                                ##STR91##      57.6 dimethylformamide- water                                                                239.5-242.2                                                                           261(37,430)                                                                         C,53.63 H, 3.18 N,14.71                                                            53.89  3.05 14.41       101                                                                                ##STR92##      50.7 dimethylformamide- water                                                                190-192 255(26,350)                                                                         C,53.63 H, 3.18 N,14.71                                                            53.70  2.97 14.90       102                                                                                ##STR93##      42.7 dimethylformamide- water                                                                202-205 375(4,200) 253(32,970)                                                              C,59.44 H, 4.05 N,21.66                                                            59.40  4.10 21.44       103                                                                                ##STR94##      44.2 dimethylformamide- water                                                                237.5-239.5                                                                           342(1,800) 264(46,530)                                                              C,59.44 H, 4.05 N,21.66                                                            59.16  4.10 21.31       104                                                                                ##STR95##      52.3 dimethylformamide- water                                                                >257(Dec.)                                                                            330(20,010)                                                                         C,59.44 H, 4.05 N,21.66                                                            59.01  3.97 21.07       105                                                                                ##STR96##      35.4 dimethylformamide- water                                                                256.5-258                                                                             257(33,080)                                                                         C,53.72 H, 3.38 N,19.57                                                            53.72  3.31 19.63       106                                                                                ##STR97##      57.1 dimethylformamide- water                                                                254-256 (Dec.)                                                                        256(36,930)                                                                         C,60.53 H, 4.48 N,20.76                                                            60.26   4.34 20.68      107                                                                                ##STR98##      47.3 dimethylformamide- water                                                                244     290(57,510)                                                                         C,67.32 H, 4.32 N,23.09                                                            67.88  4.13 21.37       108                                                                                ##STR99##      33.8 dimethylformamide- water                                                                227.5-229.5                                                                           297(32,710)                                                                         C,67.48 H, 5.03 N,17.49                                                            67.49  5.05 17.07       191                                                                                ##STR100##     35.2 dimethylformamide- water                                                                233-236 284(16,710)                                                                         C,73.15 H, 4.91 N,17.06                                                            72.70  4.97 16.63       192                                                                                ##STR101##     25.2 dimethylformamide- methanol-water                                                       231-232 252(32,920)                                                                         C,56.31 H, 3.55 N,20.52                                                            54.13  3.50             __________________________________________________________________________                                                          20.21               

4-Alkylimidazo[1,2-a]quinoxalines (Table V) were prepared by refluxingthe appropriate amide (Table I, compounds 1-33) with phosphorousoxychloride in excess pyridine during one hour. The reaction mixture wasstirred into water and sufficient azeotrope removed to form a viscousresidue which was dissolved in chloroform, dried over MgSO₄, andchromatographed through an alumina column. The chloroform was evaporatedand the product crystallized from the indicated solvent.

                                      TABLE V                                     __________________________________________________________________________     ##STR102##                                                                   4-alkylimidazo[1,2-a] quinoxalines                                                                 Recrystallization     Analysis                           No.                                                                              R            % Yield                                                                            Solvent  m.p. °C.                                                                     λmax.(Am)                                                                     Calc'd                                                                             Found                         __________________________________________________________________________    109                                                                              Ha.          63.3 sublimed 120   316(10,900)                               110                                                                              CH.sub.3     13.3 isopropyl ether                                                                        134-135                                                                             312(11,200)                                                                          C,72.11                                                                            72.18                                                                    H, 4.95                                                                             4.89                                                                    N,22.93                                                                            23.01                         111                                                                              CH.sub.3 CH.sub.2                                                                          37.6 hexane   114-115                                                                             311(10,500)                                                                          C,73.07                                                                            72.85                                                                    H, 5.62                                                                             5.83                                                                    N,21.30                                                                            21.29                         112                                                                              CH.sub.3 CH.sub.2 CH.sub.2                                                                 14.3 hexane   110-111                                                                             314(10,900)                                                                          C,73.91                                                                            73.99                                                                    H, 6.20                                                                             6.13                                                                    N,19.89                                                                            19.94                         113                                                                              CH.sub.3 (CH.sub.2).sub.3                                                                  17.6 hexane   92-93 324(8,000)                                                                           C,74.64                                                                            74.34                                                                    H, 6.70                                                                             6.74                                                                    N,18.65                                                                            18.48                         114                                                                              CH.sub.3 (CH.sub.2).sub.4                                                                  29.2 b.       63-65 314(11,300)                                                                          C,75.28                                                                            75.13                                                                    H, 7.16                                                                             7.39                                                                    N,17.56                                                                            17.43                         115                                                                              CH.sub.3 (CH.sub.2).sub.5                                                                  10.7 b.       43-45 313(10,800)                                                                          C,75.86                                                                            76.03                                                                    H, 7.56                                                                             7.63                                                                    N,16.59                                                                            16.40                         116                                                                              CH.sub.3 (CH.sub.2).sub.6                                                                  8.0  c.       54-57 313(9,400)                                                                           C,76.37                                                                            75.84                                                                    H, 7.92                                                                             7.77                                                                    N,15.72                                                                            16.43                         117                                                                              CH.sub.3 (CH.sub.2).sub.7                                                                  26.3 isopropyl ether                                                                        65-66 311(11,600)                                                                          C,76.83                                                                            76.97                                                                    H, 8.24                                                                             8.20                                                                    N,14.93                                                                            14.89                         118                                                                              CH.sub.3 (CH.sub.2).sub.8                                                                  9.5  ethyl ether-                                                                           55-57 307(12,500)                                                                          C,77.25                                                                            77.04                                              hexane                H, 8.53                                                                             8.36                                                                    N,14.22                                                                            14.52                         119                                                                              CH.sub.3 (CH.sub.2).sub.14                                                                 24.3 isopropyl ether                                                                        73-75 313(11,300)                                                                          C,79.11                                                                            79.03                                                                    H, 9.82                                                                            10.02                                                                    N,11.07                                                                            10.88                         120                                                                              CH.sub.3 (CH.sub.2).sub.16                                                                 13.7 isopropyl ether-                                                                       79-81 311(11,300)                                                                          C,79.11                                                                            79.54                                                                    H,10.14                                                                            10.12                                                                    N,10.31                                                                            10.34                         121                                                                              (CH.sub.3).sub.2 CHCH.sub.2                                                                12.6 hexanes  52-55 314(11,700)                                                                          C,74.64                                                                            74.92                                                                    H, 6.71                                                                             6.81                                                                    N,18.65                                                                            18.74                         122                                                                              CF.sub.3     50.7 isopropyl ether-                                                                       184-187                                                                             328(10,800)                                                                          C,55.70                                                                            55.94                                              chloroform            H, 2.55                                                                             2.49                                                                    N,17.72                                                                            17.64                         123                                                                              CH.sub.2CH(CH.sub.2).sub.8                                                                 9.8  hexanes  40-42 309(13,100)                                                                          C,78.14                                                                            77.92                                                                    H, 8.20                                                                             7.98                                                                    N,13.67                                                                            13.96                         124                                                                               ##STR103##  16.7 ethanol  140.5-142                                                                           312(13,100)                                                                          C,78.74  H, 5.05 N,16.20                                                           78.59  5.20 16.10             125                                                                              CH.sub.3 OCH.sub.2                                                                         3.1  toluene-hexane                                                                         96.5-97.5                                                                           312(10,600)                                                                          C,67.59                                                                            67.04                                                                    H, 5.20                                                                             5.17                                                                    N,19.71                                                                            19.93                         126                                                                               ##STR104##  14.5 ethanol  146.5-148.5                                                                         314(10,400)                                                                          C,74.17 H, 4.76 N,15.26                                                            74.28  4.61 15.09             127                                                                               ##STR105##  37.2 benzene  164-167                                                                             286(10,500)                                                                          C,79.68 H, 4.83 N,15.49                                                            80.38  4.91 15.12             128                                                                               ##STR106##  17.9 hexane   106.5-107.5                                                                         310(11,500)                                                                          C,75.31 H, 5.87 N,18.82                                                            75.32  5.84 18.75             129                                                                               ##STR107##  2.0  hexane   119-120.5                                                                           311(11,400)                                                                          C,76.46 H, 6.82 N,16.72                                                            76.65  6.76 16.58             130                                                                               ##STR108##  0.8  isopropyl ether                                                                        133-135                                                                             312(11,700)                                                                          C,77.39 H, 5.68 N,16.92                                                            77.20  6.13 16.76             __________________________________________________________________________     Notes:                                                                         a. A.M. Siminov and I.G. Urykina, Khim. Geterot Soedin., 7,570(1971)         report this compound has an mp of 124° with                            λ.sub.max..sup.MeOH (Am) = 315 (10,700).                                b. Purified by sublimation at 90°/0.15 mm Pressure.                    c. Purified by distillation at 174°-184°/0.40 mm P.       

4-Arylimidazo[1,2-a]quinoxalines (Table VI) were prepared and isolatedaccording to the general method described for the4-alkylimidazo[1,2-a]quinoxalines, except as noted in Table VI.

                                      TABLE VI                                    __________________________________________________________________________     ##STR109##                                                                   4-Arylimidazo[1,2-9]quinoxalines                                                                        %   Crystallization       Analysis                  No.                                                                              Ar                     Yield                                                                             Solvent m.p. °C.                                                                      λmax.(Am)                                                                     Calc'd                                                                              Found               __________________________________________________________________________    131                                                                               ##STR110##            34.8                                                                              benzene 145-147                                                                              328(14,100)                                                                          C,78.35 H, 4.52                                                               N,17.13                                                                             78.70  4.38                                                                   16.90               132                                                                               ##STR111##            37.2                                                                              toluene- isopropanol                                                                  149-150.5                                                                            334(22,650)                                                                          C,78.74 H, 5.05                                                               N,16.20                                                                             78.80  5.08                                                                   16.27               133                                                                               ##STR112##            35.9                                                                              isopropanol- isopropyl ether                                                          112-114                                                                              329(14,400)                                                                          C,78.74 H, 5.05                                                               N,16.20                                                                             78.53  5.19                                                                   16.20               134                                                                               ##STR113##            47.1                                                                              isopropanol                                                                           119-120                                                                              329(18,100)                                                                          C,78.74 H, 5.05                                                               N,16.20                                                                             78.32  4.73                                                                   15.93               135                                                                               ##STR114##            37.8                                                                              isopropanol                                                                           136-137                                                                              331(27,780)                                                                          C,82.22 H, 4.70                                                               N,13.07                                                                             82.06  4.38                                                                   12.89               136                                                                               ##STR115##            47.0                                                                              isooctane                                                                             112-113                                                                              332(10,411)                                                                          C,65.18 H, 3.22                                                               N,13.41                                                                             65.03  3.10                                                                   13.62               137                                                                               ##STR116##            56.7                                                                              hexanes 105-107                                                                              329(20,354)                                                                          C,79.70 H, 6.35                                                               N,13.94                                                                             79.50  6.58                                                                   13.84               138                                                                               ##STR117##            37.2                                                                              isopropanol- toluene                                                                  149-150.5                                                                            334(22,650)                                                                          C,74.17 H, 4.76                                                               N,15.26                                                                             74.18  4.79                                                                   15.33               139                                                                               ##STR118##            51.5                                                                              isopropanol                                                                           136-138                                                                              329(16,600)                                                                          C,70.81 H, 4.95                                                               N,13.76                                                                             70.61  5.06                                                                   13.56               140                                                                               ##STR119##            31.5                                                                              ethanol 173-175                                                                              328(16,280)                                                                          C,68.70 H, 3.60                                                               N,15.02                                                                             69.06  3.28                                                                   15.08               141                                                                               ##STR120##            6.8 benzene- hexanes                                                                      166-168                                                                              331(10,300)                                                                          C,68.70 H, 3.60                                                               N,15.02                                                                             68.77  3.48                                                                   14.87               142                                                                               ##STR121##            35.2                                                                              isopropanol                                                                           133-134                                                                              330(14,000)                                                                          C,68.70 H, 3.60                                                               N,15.02                                                                             68.43  3.45                                                                   14.89               143                                                                               ##STR122##            61.9                                                                              toluene 215-217.5                                                                            333(16,530)                                                                          C,61.16 H, 2.89                                                               N,13.37                                                                             60.94  2.82                                                                   13.50               144                                                                               ##STR123##            3.4 carbon tetra- chloride                                                                168-170                                                                              321(13,030)                                                                          C,61.17 H, 2.89                                                               N,13.37                                                                             60.61  2.85                                                                   13.57               145                                                                               ##STR124##            24.1                                                                              dimethyl- formamide- water                                                            161.5-164.5                                                                          319(10,200)                                                                          C,59.28 H, 3.11                                                               N,12.96                                                                             58.75  3.03                                                                   12.90               146                                                                               ##STR125##            13.4                                                                              dimethyl-  formamide- water                                                           172    329(12,900)                                                                          C,59.28 H, 3.11                                                               N,12.96                                                                             59.34  3.13                                                                   13.23               147                                                                               ##STR126##            39.1                                                                              isopropanol                                                                           183-185                                                                              328(14,500)                                                                          C,72.99 H, 3.83                                                               N,15.96                                                                             73.00  4.06                                                                   15.77               148                                                                               ##STR127##            15.0                                                                              ethanol 190-192                                                                              222(48,000)                                                                          C,70.58 H, 3.83                                                               N,14.52                                                                             70.54  3.71                                                                   14.67               149                                                                               ##STR128##            53.3                                                                              dimethyl- formamide- water                                                            257.5-259.5                                                                          335(14,900)                                                                          C,75.54 H, 3.73                                                               N,20.73                                                                             75.15  3.85                                                                   20.66               150                                                                               ##STR129##            59.8                                                                              2-ethoxyethanol                                                                       220.5-222.5                                                                          333(13,850)                                                                          C,66.20 H, 3.47                                                               N,19.30                                                                             66.10  3.48                                                                   19.53               151                                                                               ##STR130##            40.3                                                                              toluene 249-252                                                                              346(15,269)                                                                          C,66.20 H, 3.47                                                               N,19.30                                                                             66.10  3.44                                                                   19.28               152                                                                               ##STR131##            52.5                                                                              dimethyl- formamide                                                                   283-285                                                                              340(10,880)                                                                          C,57.30 H,  2.71                                                              N,20.89                                                                             57.08  2.74                                                                   21.11               153                                                                               ##STR132##            75.7                                                                              dimethyl- formamide- water                                                            198-199.5                                                                            369(23,470)                                                                          C,73.83 H, 4.65                                                               N,21.53                                                                             73.48  4.69                                                                   21.54               154                                                                               ##STR133##            61.9                                                                              dimethyl- formamide- water                                                            130-133                                                                              326(14,830)                                                                          C,73.83 H, 4.65                                                               N,21.53                                                                             73.56  4.78                                                                   21.69               155                                                                               ##STR134##            58.0                                                                              ethylacetate- hexane                                                                  214-217                                                                              342(27,700)                                                                          C,68.88 H, 4.66                                                               N,17.85                                                                             68.46  4.99                                                                   17.76               156                                                                               ##STR135##            13.9                                                                              dimethyl- formamide- water                                                            237.5-240                                                                            345(32,350)                                                                          C,68.24 H, 3.90                                                               N,13.84                                                                             68.54  3.90                                                                   14.00               173                                                                               ##STR136##            32.3                                                                              ethanol 155-157                                                                              321(13,090)                                                                          C,72.99 H, 3.83                                                               N,15.96                                                                             72.44  3.83                                                                   16.14               157                                                                               ##STR137##            56.6                                                                              dimethyl- formamide- water                                                            134.5-136                                                                            332(14,260)                                                                          C,59.28 H, 3.11                                                               N,12.96                                                                             59.25  3.04                                                                   13.11               158                                                                               ##STR138##            47.5                                                                              dimethyl- formamide- water                                                            132.5-134                                                                            330(13,970)                                                                          C,72.99 H, 3.83                                                               N,15.96                                                                             73.00  3.79                                                                   15.84               159                                                                               ##STR139##            52.7                                                                              ethanol 113-114.5                                                                            329(16,500)                                                                          C,74.17 H, 4.76                                                               N,15.26                                                                             74.09  4.71                                                                   15.05               160                                                                               ##STR140##            10.62                                                                             chloroform                                                                            159-161.5                                                                            323(15,290)                                                                          C,81.34 H, 4.43                                                               N,14.23                                                                             81.29  4.41                                                                   14.22               161                                                                               ##STR141##            43.2                                                                              benzene 154.5-156.5                                                                          340(21,800)                                                                          C,81.34 H, 4.44                                                               N,14.23                                                                             81.19  4.57                                                                   13.92               162                                                                               ##STR142##            25.4                                                                              isopropanol                                                                           210-215                                                                              343(23,800)                                                                          C,68.81  H, 4.69                                                              N,15.04                                                                             68.99  4.63                                                                   14.92               163                                                                               ##STR143##            84.2                                                                              ethanol 158-160                                                                              333(14,950)                                                                          C,71.28 H, 4.32                                                               N,13.85                                                                             71.31  4.44                                                                   13.85               164                                                                               ##STR144##            80.3                                                                              ethanol 116-118                                                                              335(15,100)                                                                          C,72.49 H, 5.17                                                               N,12.68                                                                             72.38  5.42                                                                   12.36               165                                                                               ##STR145##            62.6                                                                              ethanol 90.5-93.5                                                                            335(15,100)                                                                          c,75.15 H, 7.03                                                               N,10.11                                                                             74.87  7.16                                                                   9.94                166                                                                               ##STR146##            45.85                                                                             chloroform                                                                            154-155.5                                                                            344(27,240)                                                                          C,76.38 H, 8.51                                                               N,11.14                                                                             76.58  8.35                                                                   10.81               193                                                                               ##STR147##            29.80                                                                             ethanol 150-152                                                                              342(22,900)                                                                          C,74.72 H, 5.23                                                               N,14.52                                                                             74.37   5.17                                                                  14.33               196                                                                               ##STR148##            8.2 dimethyl- formamide- water                                                            178-181                                                                              330(27,300)                                                                          C,51.77 H, 2.72                                                               N,11.32                                                                             51.89  2.68                                                                   11.46               219                                                                               ##STR149##            37.1                                                                              toluene 151.5-153.5                                                                          333(21,000)                                                                          C,78.32 H, 4.48                                                               N,12.45                                                                             78.32  4.63                                                                   12.22               220                                                                               ##STR150##            35.1                                                                              benzene 151.5-153.5                                                                          337(22,200)                                                                          C,75.19 H, 4.66                                                               N,11.44                                                                             75.42  4.58                                                                   11.46               221                                                                               ##STR151##            33.3                                                                              ethanol-water                                                                         >330°                                                                         343(22,700)                                                                          C,72.92 H, 4.45                                                               N,11.60                                                                             73.21  4.31                                                                   11.74               222                                                                               ##STR152##            28.2                                                                              ethanol 83-85  348(24,600)                                                                          C,72.04 H, 5.74                                                               N,12.60                                                                             71.64  5.68                                                                   12.62               194                                                                               ##STR153##            22.6                                                                              toluene 164-165.5                                                                            339(19,400)                                                                          C,68.05 H, 5.11                                                               N,12.53                                                                             67.70  5.03                                                                   12.32               __________________________________________________________________________      a. U.S. Pat. No. 3,887,566 describes this compound as having a m.p. of       154-157° C.                                                             b. Prepared by refluxing aquimolar amounts of the 2aminophinyl-imidazole     and phthalic anlydride in toluene for one and onehalf hours. Upon cooling     the product separated out of solution.                                         c. Prepared by catalytic hydrogenation with 10% palladium on carbon of a     dimethylformamide solution of the nitro analog; crude product precipitate     with water.                                                                    d. Prepared by treating compound 153 in pyridine with the appropriate        acid chloride followed by precipitation with water.                            e. Prepared by HI cleavage of compound No. 138.                               f. Prepared by treating the lithium salt of compound No. 162 with the        appropriate acid chloride in DMF followed by precipitation with water.         g. Prepared by treating compound No. 151 with the appropriate nucleophil     according to the method of Kornblum et al, J. Org. Chem., 41, 1560(1976).      h. Prepared by HI cleavage of compound 220.                             

The 4-Alkylaminoimidazo[1,2-a]quinoxalines (Table VII) were prepared bytreating the corresponding alkylureylenes (Table III) with phosphorousoxychloride and pyridine during one-half hour at reflux temperatures.The reaction mixture was poured into cold water and the excess pyridinewas removed by azeotropic distillation. The crude product was dissolvedin chloroform and pass through an alumina columa. After evaporation ofthe chloroform, the solid was crystallized from the indicated solventand obtained in the indicated yield.

                                      TABLE VII                                   __________________________________________________________________________     ##STR154##                                                                   4-Alkylaminoimidazo[1,2-a]quinoxalines 1,2-a}quinoxalines                                  %   Crystallization       Analysis                               No.                                                                              R         Yield                                                                             Solvent   m.p. °C.                                                                     λmax.(Am)                                                                    Calc'd                                                                             Found                             __________________________________________________________________________    167                                                                               ##STR155##                                                                             4.89                                                                              hexane    98.5-101.5                                                                          335(11,700)                                                                         C,72.15 H, 6.81 N,21.04                                                            72.02  6.75 20.81                 168                                                                              CH.sub.3 (CH.sub.2).sub.2 CH.sub.2                                                      28.33                                                                             isopropyl ether                                                                         102-104                                                                             332(11,480)                                                                         C,69.97                                                                            70.12                                                                    H, 6.71                                                                             6.71                                                                    N,23.31                                                                            23.21                             169                                                                              CH.sub.3 (CH.sub.2).sub.2                                                               7.5 isopropyl ether                                                                         72-74 317(15,800)                                                                         C,69.00                                                                            69.14                                                                    H, 6.24                                                                             6.35                                                                    N,24.76                                                                            24.60                             __________________________________________________________________________

4-Arylaminoimidazo[1,2-a]quinoxalines (Table VIII) were prepared bytreating the corresponding arylaureylenes (Table IV) with an equimolaramount of phosphorous oxychloride in refluxing pyridine during one hour.The cooled reaction mixture was stirred into cold water, and the crudesolid which separated was dissolved in chloroform, dried and passedthrough an alumina column. The chloroform was evaporated and the crudesolid was crystallized as indicated in Table VIII.

                                      TABLE VIII                                  __________________________________________________________________________     ##STR156##                                                                   4-Arylaminoimidazo{1,2-a}quinoxalines                                                              %   Crystallization         Analysis                     No.                                                                              Ar                Yield                                                                             Solvent     m.p. °C.                                                                     λmax.(Am)                                                                    Calc'd                                                                             Found                   __________________________________________________________________________    170                                                                               ##STR157##       7.2 ethanol-water                                                                             120-123                                                                             304(13,800)                                                                         C,72.57 H, 4.76 N,21.16                                                            72.67  4.71 20.88       171                                                                               ##STR158##       13.1                                                                              methanol- chloroform                                                                      151   334(20,700)                                                                         C,74.43 H, 5.14 N,20.42                                                            74.16  5.06 20.09       172                                                                               ##STR159##       11.7                                                                              methanol- chloroform                                                                      153-155                                                                             330(20,200)                                                                         C,74.43 H, 5.14 N,20.42                                                             73.23  5.26 20.02      174                                                                               ##STR160##       13.6                                                                              methanol- chloroform                                                                      176.5-178                                                                           330(22,200)                                                                         C,65.26 H, 3.75 N,19.02                                                            65.04  3.77 18.91       175                                                                               ##STR161##       10.9                                                                              methanol- chloroform                                                                      178.5-180.5                                                                         334(33,600)                                                                         C,58.38 H, 3.06 N,17.02                                                            58.15  3.06 17.09       176                                                                               ##STR162##       18.2                                                                              toluene- chloroform                                                                       193.5-195                                                                           332(4,500)                                                                          C,49.76 H, 2.87 N,14.51                                                            49.72  3.10 14.39       177                                                                               ##STR163##       11.5                                                                              ethanol     196.5-198.5                                                                         324(16,600)                                                                         C,56.66 H, 3.27 N,16.52                                                            56.69  3.24 16.43       178                                                                               ##STR164##       15.0                                                                              methanol- chloroform                                                                      184-185.5                                                                           329(24,100)                                                                         C,56.66 H, 3.27 N,16.52                                                            56.26  3.20 16.54       179                                                                               ##STR165##       10.52                                                                             dimethylformamide water                                                                   122-124                                                                             343(19,600)                                                                         C,63.27 H, 3.98 N,18.45                                                            62.94  4.19  18.58      180                                                                               ##STR166##       13.0                                                                              ethanol-dimethyl- formamide                                                               139   339(19,810)                                                                         C,69.05 H, 3.98 N,20.13                                                            68.88  4.02 20.13       181                                                                               ##STR167##       9.4 isopropanol 148.5-149.5                                                                         343(20,230)                                                                         C,69.05 H, 3.98 N,20.13                                                            68.92  4.00 20.14       182                                                                               ##STR168##       3.1 isopropanol 139.5-141                                                                           331(18,030)                                                                         C,69.05 H, 3.98 N,20.13                                                            68.50  3.92 19.86       183                                                                               ##STR169##       16.58                                                                             dimethylformamide- water                                                                  166-168.5                                                                           347(21,730)                                                                         C,56.66 H, 3.27 N,16.52                                                            56.31  3.25 16.56       184                                                                               ##STR170##       11.4                                                                              dimethylformamide- water                                                                  207-209                                                                             366(22,410)                                                                         C,70.33 H, 4.86 N,19.30                                                            70.61  5.11 19.11       185                                                                               ##STR171##       8.3 dimethylformamide- water                                                                  116.5-117.5                                                                         335(21,820)                                                                         C,70.33 H, 4.86 N,19.30                                                            70.16  5.28 19.31       186                                                                               ##STR172##       14.12                                                                             dimethylformamide- water                                                                  147-149                                                                             339(18,540)                                                                         C,70.33 H, 4.86 N,19.30                                                            70.14  4.98 19.09       187                                                                               ##STR173##       2.0 isopropanol-dimethyl- formamide                                                           195-197                                                                             341(20,370)                                                                         C,60.28 H, 3.95 N,21.97                                                            60.21  3.88 21.63       188                                                                               ##STR174##       36.4                                                                              dimethylformamide- water                                                                  241-243.5                                                                           400(8,960)                                                                          C,62.95 H, 3.63 N,22.94                                                            62.62  3.63 22.68       189                                                                               ##STR175##       33.1                                                                              dimethylformamide- water                                                                  323-324.5                                                                           368(23,670)                                                                         C,62.95 H, 3.63 N,22.94                                                            62.73  3.73 22.81       195                                                                               ##STR176##       11.61                                                                             dimethylformamide- water                                                                  138.5-141                                                                           335(22,900)                                                                         C,74.99 H, 4.58 N,15.90                                                            75.02  4.66 75.02       197                                                                               ##STR177##       5.52                                                                              dimethylformamide- water                                                                  143-145                                                                             330(18,000)                                                                         C,74.43 H, 5.15 N,20.42                                                            74.63  5.16 20.09       198                                                                               ##STR178##       10.91                                                                             dimethylformamide                                                                         163.5-165.5                                                                         337(18,800)                                                                         C,74.98 H, 5.59 N,19.43                                                            74.69  5.56 19.43       199                                                                               ##STR179##       15.29                                                                             dimethylformamide- water                                                                  81-83 333(20,800)                                                                         C,73.83 H, 5.51 N,19.13                                                            73.87  5.49 18.88       200                                                                               ##STR180##       13.81                                                                             dimethylformamide- water                                                                  124.5-127                                                                           335(23,200)                                                                         C,73.83 H, 5.51 N,19.13                                                            74.14  5.47 19.02       201                                                                               ##STR181##       16.96                                                                             isopropanol- water                                                                        89.5-91.5                                                                           335(21,000)                                                                         C,73.83 H, 5.51 N,19.13                                                            74.14  5.47 19.02       202                                                                               ##STR182##       11.50                                                                             methanol- chloroform                                                                      187-190                                                                             342(24,200)                                                                         C,76.29 H, 4.56 N,17.80                                                            76.58  4.52 17.58       203                                                                               ##STR183##       12.50                                                                             dimethylformamide- water                                                                  120.5-123                                                                           340(20,300)                                                                         C,68.99 H, 5.15 N,17.88                                                            68.32  5.32 17.61       204                                                                               ##STR184##       21.39                                                                             dimethylformamide- water                                                                  102.5-107                                                                           340(19,600)                                                                         C,62.20 H, 3.38 N,17.07                                                            61.56  3.34 17.46       205                                                                               ##STR185##       8.5 dimethylformamide- water                                                                  90-97 341(26,400)                                                                         C,65.68 H, 4.62 N,18.02                                                            65.56  4.57 17.88       206                                                                               ##STR186##       21.39                                                                             dimethylformamide- water                                                                  129-130                                                                             347(20,300)                                                                         C,62.20 H, 3.38 N,17.07                                                            61.56  3.34 17.46       207                                                                               ##STR187##       11.49                                                                             dimethylformamide- water                                                                  178.5-179.5                                                                         324(25,500)                                                                         C,56.29 H, 2.78 N,15.45                                                            55.86  2.72 15.37       208                                                                               ##STR188##       7.52                                                                              dimethylformamide- water                                                                  172.5-173.5                                                                         345(24,900)                                                                         C,56.29 H, 2.78 N,15.45                                                            56.13  2.72 15.35       209                                                                               ##STR189##       15.18                                                                             dimethylformamide- water                                                                  170-172                                                                             332(23,800)                                                                         C,65.18 H, 4.18 N,17.89                                                            65.35  4.15 17.91       210                                                                               ##STR190##       13.56                                                                             dimethylformamide- water                                                                  171.5-173                                                                           337(17,300)                                                                         C,64.86 H, 3.40 N,18.91                                                            64.92  3.51 19.09       211                                                                               ##STR191##       10.78                                                                             dimethylformamide- water                                                                  259.5-261.5                                                                         342(23,200)                                                                         C,56.82 H, 3.28 N,16.57                                                            56.76  3.07 16.57       212                                                                               ##STR192##       7.22                                                                              dimethylformamide- water                                                                  198-200                                                                             343(18,400)                                                                         C,61.45 H, 3.22 N,17.92                                                            61.35  3.27 17.81       213                                                                               ##STR193##       3.04                                                                              methanol-chloroform                                                                       229-231                                                                             341(19,900)                                                                         C,58.63 H,  3.15                                                                   58.50  3.06 21.20       214                                                                               ##STR194##       4.18                                                                              methanol-chloroform                                                                       168-170                                                                             344(21,400)                                                                         C,63.06 H, 4.12 N,21.63                                                            62.97  4.08 21.34       215                                                                               ##STR195##       19.43                                                                             dimethylformamide- water                                                                  271-273                                                                             346(19,600)                                                                         C,56.57 H, 2.97 N,20.61                                                            56.44  2.90 20.51       216                                                                               ##STR196##       5.96                                                                              dimethylformamide- water                                                                  224-226.5                                                                           349(34,700)                                                                         C,70.48 H, 3.91 N,24.17                                                            70.89  3.94 24.09       217                                                                               ##STR197##       2.31                                                                              isopropanol 95-96.5                                                                              --   C,75.47 H, 6.00 N,18.53                                                            75.08  6.34             __________________________________________________________________________                                                          18.53               

Various compounds of this invention display anti-fungal and anti-yeastactivity. Thus, for example, they have been found to be effectiveagainst such organisms as Candida albicans (ATCC No. 10231), Candidatropicalis, Aspergillus niger (ATCC No. 16404), Trichophytonmentagrophytes (ATCC No. 8757 and 9129), Trichophyton rubrum (ATCC No.10218 and 14001) and Trichophyton ajelloi.

The antifungal activity of compounds of this invention indicate theirusefulness against dermatomycosis such as tinea capitis, tinea favosa,tinea barbae, tinea corporis, tinea imbricata, tinea cruris, tineapedis, tinea manus, tinea unquium and various types of candidiasis suchas glossitis, stomatitis, chelitis, perleche, vaginitis and balanitis.

When the compounds of the present invention are used for antifungalmedical purposes, they will usually be incorporated in a suitablepharmaceutical carrier. These antifungal preparations may take the formof solutions, lotions, creams, ointments, etc. The quantity ofantifungal agent of this invention that will be contained in suchpreparations may vary somewhat. Ordinarily, however, it will constituteabout 0.5% to 10.0% by weight based on the total weight of thepreparation.

In Table IX below are listed the antifungal activity of a number ofcompounds encompassed in the present invention. These were determined bythe agar dilution method as described in Chapters 2 and 3 of Methods inMicrobiology, Vol. 7B, edited by J. R. Norris and D. W. Ribbons,Academic Press, New York, 1972.

                  TABLE IX                                                        ______________________________________                                        Antifungal Activity                                                           Parts Per Million Inhibitions of                                              Fungus and Yeast Species                                                      Com-                               T.                                         pound C.       C.       A.   T.    menta-  T.                                 No.   albicans tropicalis                                                                             niger                                                                              ajelloi                                                                             grophytes                                                                             rubrum                             ______________________________________                                        20                           100   100                                        136                                100                                        40    100      100           100   100                                        35                           100   16                                         39                           100   100                                        133   100      100            8    8       8                                  134                          100   16                                         139                                100                                        137                          100   100                                        135                          100   100                                        142                                100                                        132                          100   100                                        138                          100   100                                        130   100      100           100   100                                        113   100      100                 100                                        9                                  16      16                                 10                                 16      16                                 116                                16      16                                 127                                16      16                                 109                                128     32                                 114                                16      1                                  118                                256     4                                  123                                        2                                  131                                16      2                                  140                                        <0.5                               151                                        1                                  191                                        8                                  120                                        1                                  8                                  8       8                                  16                                 4       2                                  110                     128        128     64                                 122                                        32                                 112                                128     64                                 153            100                                                            124   100      100           100   100     8                                  58                           100   100     100                                59                                         100                                62                           100   100     100                                126                          100   100     100                                145                          100   100     100                                159                          100   100     100                                160                          100   100     100                                163                          100   100     100                                164                          100   100     100                                165                          100   100     100                                167                          100   100     100                                168                          100   100     100                                169                          100   100     100                                173                          100   100     100                                179                          100   100     100                                182                                        100                                184                          100   100     100                                185                          100   100     100                                186                          100   100     100                                189                          100           100                                187                          100           100                                123                                        16                                 129                           16   16      8                                  ______________________________________                                    

A number of the compounds encompassed in the present invention have beenfound to have immunosuppressant action. Of those tested, most of theseare of the 4-substituted imidazo[1,2-a]quinoxaline type described informula I above, although a couple are of the1-(2-acylaminophenyl)imidazole type shown in formula II. Because theyexhibit this activity, they are indicated for use in the treatment ofthose diseases that the prior art recognizes may be helped by theadministration of immunosuppressants. These include such conditions as:glomerulonephritis, serum sickness, organ transplant, rheumatoidarthritis, systemic lupus erythematosis, ulcerative colitis, chronicactive hepatitis, multiple sclerosis, heterografts or homografts inburns, psoriatic arthritis, urticaria, respiratory allergies, i.e.asthma, hayfever; scleraclerma, mycosis fungoides, dermatomyositis,psoriasis and contact dermatitis (including poison ivy).

The dosage level for administering the immunosuppressants of the presentinvention will vary with the particular compound that is to beadministered. In general, this will be at about the same level of theprior art immunosuppressants. For the most part, when the presentimmunosuppressants are administered orally or intraveneously, the dailydose would be in the range of about 0.1 mg. to 15 mg./per kilogram ofbody weight. When other mode of administration are employed, e.g. depotinjections, implants, etc. the dose may be considerably higher i.e. upto about 100 mg./kg of body weight in a single injection.

The immunosuppressant activities of the compounds of this invention weredetermined via the hemolysin test in mice and by the delayedhypersensitivity test. The hemolysin test used is that described inMethods in Immunology, edited by D. H. Campbell et al, W. A. Benjamin,New York 1963 pages 172-175, and measures humeral or antibody response.The delayed hypersensitivity test measures the effect of a test compoundon the ability of a subject mouse to mount a cell-mediated immuneresponse to the antigen, Mycobacterium tuberculosis H37Ra. The mouse issensitized to the antigen by subcutaneous administration in the base ofthe tail. The development of the delayed hypersensitivity response maybe measured at any time beginning six days after sensitization but isusually done on the ninth day as follows: The right hind paw is injectedwith purified protein derivative (tuberculin) while the left hind paw(control) receives physiological saline. Both paw volumes are measuredafter twenty-four hours and significant increase in the volume of theright hind paw is taken as a measure of an effective delayedhypersensitivity response. All compounds were administered by thesubcutaneous route.

The results of these studies are summarized in Table X below. Theexpression HL(ED₅₀) mg./kg. s.c. is an expression of the number ofmilligrams per kilogram of body weight of the drug administeredsubcutaneously required to reduce the antibody activity by 50% whencompared with a control. In this case, the lower the HL(ED₅₀) value fora drug the more effective immunosuppressant it is.

The D.H.S. (ED₆₀) mg./kg. s.c. value appearing in column 3 is anexpression of the effectiveness of the drug in reducing the edema thataccompanies the cell-mediated immune response. It is a measure of thenumber of milligrams per kilogram of body weight of the drugadministered subcutaneously which is required to reduce the edema of thecell-mediated immune response by 60% when compared to the control.Again, the lower the D.H.S. (ED₆₀) value the more effective is the drugas an immunosuppressant for the cell-mediate immune response.

                  TABLE X                                                         ______________________________________                                        Compound    HL(ED.sub.50)                                                                              D.H.S. (ED.sub.60)                                   No.         mg/kg,s.c.   mg/kg,s.c                                            ______________________________________                                        151         0.3          1.52                                                 140         0.26         1.15                                                 131         18           81                                                   116         >50          56                                                   117         >50          46                                                   118         >50          43                                                   109         >50          >50                                                  110         --           50                                                    3          50           50                                                   66          46           >50                                                  147         0.027        1.7                                                  134         0.5          7.2                                                  137         <0.125       3.2                                                  135         0.033        0.22                                                 142         0.20         4.2                                                  136         2.7          >50                                                  133         0.75         32                                                   139         3.0          >50                                                  138         0.72         27                                                   127         >50          36                                                   170         6.6          >50                                                  150         22           >50                                                  143         0.36         1.3                                                  174         0.61         8.0                                                  171         0.96         59.0                                                 175         0.09         5.9                                                  178         11.0         46.0                                                 196         0.42         45.0                                                 197         1.6          37                                                    3          50.0         50.0                                                 169         46           >50.0                                                146         0.11         3.1                                                  153         1.2          5.7                                                  149         0.16         8.8                                                  126         35.0         >50.0                                                177         13.0         >50.0                                                182         1.1          --                                                   162         13.0         --                                                   173         --           40                                                   159         3.0          27                                                   181         16.0         --                                                   180         5.6          --                                                   183         0.39         15                                                   158         1.0          7.6                                                  157         0.39         12                                                   218         1.5          25                                                   219         2.5          >32                                                  220         2.3          11                                                   222         1.0          >32                                                  ______________________________________                                         >50 means that it would take more than 50 mg./kg. of drug to reduce the       humeral antibody activity by 50% or to reduce edema of the cell mediated      immune response by 60%. Since these values are higher than is of practica     interest from a clinical point of view, no further testing was doe for        these materials.                                                         

A number of compounds encompassed in the present invention displaynon-steroidal anti-inflammatory properties. This appears to be generallythe case for the 4-substituted imidazo[1,2-a]quinoxalines of formula 1above and the 1-(2-acylaminophenyl)imidazoles of formula II. Because ofthis characteristic, they are indicated for use in the treatment ofdiseases that the prior art recognizes may be helped by theadministration of non-steroidal anti-inflammatory compounds. Theseinclude such conditions as ichthyosis, psoriasis, alopecia, atopiceczemas, etc.

The dosage level for administering the anti-inflammatory agents of thepresent invention may vary somewhat depending on the particular drugselected, the disease being treated and the mode of administration. Ingeneral, however, when used for topical application, the compounds aredistributed in a pharmaceutical vehicle suitable for topicalapplication. In these compositions, the anti-inflammatory agent of thisinvention will comprise about 0.5% to 15.0% by weight based on the totalweight of the composition.

The anti-inflammatory agents of the present invention may also beadministered orally, intraveneously, subcutaneously, intramuscularly,and intradermally. In these cases, the daily dosage will be in the rangeof from 0.5 mg. to 20 mg. per kilogram of body weight of the activeanti-inflammatory agents of this invention.

The anti-inflammatory activity of representative compounds of thisinvention was determined by the rat paw edema assay both by localadministration (Table XI below) and by oral dosing (Table XII below).For the oral dosing, the procedure of C. A. Winter, E. A. Risley and G.W. Nuss, Proc. Soc. Exp. Biol. Med. 111, 544 (1962) was employed withmeasurement taken four hours after the drug was administered. The localadministration tests were carried out similarly except the irritant(carrageenan) and the test compound were injected simultaneously at timezero.

Tables XI and XII report the anti-inflammatory activity of the compoundstested as % difference in the edema or swelling as compared with thecontrol. These Tables also give the response in many instances of morethan one dose level of the same drug.

                  TABLE XI                                                        ______________________________________                                        Rat Paw Edema Assay,                                                          Local Administration                                                          (injected directly into paw)                                                  % Difference from Control                                                     Compound No.                                                                             1μg   10μg  100μg                                                                             100 mg/kg                                 ______________________________________                                        148        -32.6    -53.5    -14.3    -39                                     109        -30.8    -3.9     +31.6                                            114        -68.2    -30.0    -131.6                                           117                                                                           110                                   -74                                     122                                   -61                                      49                                   -35                                      7                                    -22                                      51                                   -57                                     140                                   -78                                     ______________________________________                                    

                  TABLE XII                                                       ______________________________________                                        Rat Paw Edema Assay, Oral Dosing                                                         %Difference from Control                                           Compound No. 100 mg/kg     400 mg/kg                                          ______________________________________                                        Indomethacin -65                                                              phenybutazone                                                                              -76                                                              Aspirin      -57                                                              114          -61                                                              110          -43                                                              122          -61                                                              148          -52                                                              49           -35                                                              7            -52                                                              51           -57                                                              140          -35                                                              131          -52                                                              10           -30                                                              39           -50                                                              133          -17                                                              137          -26                                                              112          -17           -68                                                111          -43                                                              121          -61                                                              147          -39                                                              134          -43                                                              139          -22           -25                                                132          -76                                                              150          -30                                                              144          -26                                                              115          +70           -25                                                117          -7            -18                                                123          0             -50                                                116          +104          -18                                                136          -9            -25                                                8            -22           -13                                                29           -24           -25                                                14           -52                                                              20           -59                                                              38           -41                                                              57           -35                                                              50           -20           -33                                                45           -33                                                              40           -43                                                              35           -50                                                              37           -35                                                              18           -28                                                              15           -24           -5                                                 55           -26                                                              52           -26                                                              2            -26           +43                                                23           -46                                                              25           -30                                                              30           +9            -33                                                36           -7            -68                                                42           -9            -25                                                24           -17           -25                                                109          -17                                                              71           -22                                                              75           -30                                                              68           -26                                                              73           -22                                                              128          -39                                                              129          -30                                                              ______________________________________                                    

What is claimed is:
 1. A method for inhibiting fungal growth comprisingcontacting a fungus sensitive thereto with an amount sufficient toinhibit the growth of such fungus of an imidazo[1,2-a]quinoxalinesubstituted at the 4-position by a hydrogen, an alkyl group of from 1 to17 carbon atoms, 9-decenyl, a trifluoromethyl group, a benzyl group, acycloalkyl group of from 4 or 6 carbon atoms, a styryl group, a phenylgroup, and a phenyl group substituted by methyl, chloro, nitro or amino,in a suitable carrier therefor.
 2. The method for inhibiting fungalgrowth according to claim 1 wherein said imidazo[1,2-a]quinoxaline ispresent in an amount of from about 0.5% to 10% by weight.